Estrogen receptor-positive (ER) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER breast cancer. Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER breast cancer models, including several patient-derived xenograft models. Elacestrant induces the degradation of ER, inhibits ER-mediated signaling and growth of ER breast cancer cell lines and , and significantly inhibits tumor growth of multiple PDX models. Furthermore, we demonstrate that elacestrant in combination with palbociclib or everolimus can lead to greater efficacy in certain contexts. Finally, elacestrant exhibits significant antitumor activity both as a single agent and in combination with palbociclib in two patient-derived breast cancer xenograft models harboring mutations. These data underscore the potential clinical utility of elacestrant as a single agent and as a combination therapy, for both early- and late-stage ER disease. .